The Ly49 and KIR families are comprised of both inhibitory and activating receptors; the latter interacting and signaling through DAP12. We have continued our dissection of the proximal events associated with DAP12 signaling over the review period. The result of this work includes the definition of an apparent defect in DAP12 signaling in mice of the 129/Sv background that can profoundly effect the analysis of gene targeted mice, delineation of two levels of regulation of DAP12 signaling by CD45 (signal initiation and dephosphorylation of DAP-12 itself), and most recently, dissection of the overlapping use of the non-catalytic adaptor proteins Linker for Activation of T cells (LAT) and the Linker for Activation of B cells (LAB). TREM-1 regulates sepsis whereas TREM-2 can control the development of DC, microglia and osteoclasts. Our studies of the TREM cluster have led to publications regarding; 1) the identification of TREM-like transcript-1 (TLT-1), a protein that does not couple to DAP-12 but instead interacts with SHP-1; 2) characterization of TLT-1 as a platelet specific receptor sequestered in alpha granules; and 3) identification of soluble TLT-1 in serum, and solution of the crystal structure of the extracellular domain. We have also targeted TLT-1 in mice, shown its role in platelet aggregation in vitro, and defined some proteins that interact with it. Although platelets and thrombosis can regulate inflammation, cancer growth and metastasis, and adaptive immunity, we have chosen not to propose further TLT-1 studies under our base allocation here. If however, sufficient resources were available, we would continue biochemical study of TLT-1. We are currently, evaluating our TLT-1-/- mice in collaboration with a former fellow from our lab.